Aspirin and the thienopyridine clopidogrel have become the mainstay of anti-platelet therapy for prevention of complications of atherosclerotic vascular disease. In recent years, we and others have demonstrated that a significant minority of patients do not achieve the anticipated level of inhibition of platelet aggregation to either aspirin or clopidogrel. Despite several studies that have characterized aspirin and clopidogrel resistance in terms of their natural history and propensity for adverse clinical events, the genomic or proteomic basis for this phenomenon has not yet been defined. Based on preliminary data generated by our group and others, we hypothesize that specific genomic variations account for the marked heterogeneity in response to anti-platelet agents. The principal goal of this project will be to assess whether genotype or platelet phenotype is more predictive of response to antiplatelet therapy and clinical outcome. In Aim 1, we will utilize a haplotype map of the P2RY12 ADP receptor gene to evaluate the significance of genetic heterogeneity with respect to clinical evidence of resistance to clopidogrel in 5000 patients from the CHARISMA trial. In Aim 2, we plan to validate our observation of an association of the P2RY1 C/T893 single nucleotide polymorphism (SNP) with aspirin resistance. We will also assess other SNPs that may be linked to aspirin resistance using a candidate gene and platelet transcriptome approach. In Aim 3, using a prospectively enrolled cohort of patients (n=500) undergoing coronary intervention treated with aspirin + clopidogrel, we will determine whether the genomic abnormalities associated with aspirin and/or clopidogrel resistance identified in Aims 1 and 2 are associated with adverse peri-procedural and one year outcomes. We will further evaluate whether specific phenotypes are important in determining response to clopidogrel and aspirin therapy. At 30 days, patients with suboptimal functional aspirin or clopidogrel effect will have drug doses increased for 30 days and followed to 60 days post-procedure for serial measurement of platelet function. The significance of this project on the practice of medicine is particularly critical. More than 20 million individuals in the US take aspirin for prophylaxis of heart attack, stroke and death. Clopidogrel is prescribed yearly in >2 million patients in the US. Currently, there is no way to individually adjust the dose of anti-platelet therapy according to the genomic profile or functional platelet assay. The results of this project will illuminate the specific pathways to make dose and agent selection individualized and promote rational use of anti-platelet agents in the future.